Format

Send to

Choose Destination
Cardiovasc Res. 2016 Feb 1;109(2):331-43. doi: 10.1093/cvr/cvv272. Epub 2015 Dec 16.

Toll-like receptor 3 signalling mediates angiogenic response upon shock wave treatment of ischaemic muscle.

Author information

1
Department of Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria.
2
Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
3
Department of Internal Medicine III, Innsbruck Medical University, Innsbruck, Austria.
4
Department of Anatomy and Cell Biology, Vienna Medical University, Vienna, Austria.
5
Faculty of Medicine, Philipps University Marburg, Marburg, Germany.
6
Department of Anesthesiology and Operative Intensive Care Medicine, Kepler University Hospital, Linz, Austria patrick.paulus@gmx.net.

Abstract

AIMS:

Shock wave therapy (SWT) represents a clinically widely used angiogenic and thus regenerative approach for the treatment of ischaemic heart or limb disease. Despite promising results in preclinical and clinical trials, the exact mechanism of action remains unknown. Toll-like receptor 3, which is part of the innate immunity, is activated by binding double-stranded (ds) RNA. It plays a key role in inflammation, a process that is needed also for angiogenesis. We hypothesize that SWT causes cellular cavitation without damaging the target cells, thus liberating cytoplasmic RNA that in turn activates TLR3.

METHODS AND RESULTS:

SWT induces TLR3 and IFN-β1 gene expression as well as RNA liberation from endothelial cells in a time-dependant manner. Conditioned medium from SWT-treated HUVECs induced TLR3 signalling in reporter cells. The response was lost when the medium was treated with RNase III to abolish dsRNAs or when TLR3 was silenced using siRNAs. In a mouse hind limb ischaemia model using wt and TLR3(-/-) mice (n = 6), SWT induced angiogenesis and arteriogenesis only in wt animals. These effects were accompanied by improved blood perfusion of treated limbs. Analysis of main molecules of the TLR3 pathways confirmed TLR3 signalling in vivo following SWT.

CONCLUSION:

Our data reveal a central role of the innate immune system, namely Toll-like receptor 3, to mediate angiogenesis upon release of cytoplasmic RNAs by mechanotransduction of SWT.

KEYWORDS:

Angiogenesis; Shock wave therapy; Toll-like receptor 3

PMID:
26676850
DOI:
10.1093/cvr/cvv272
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center